State Key Laboratory of Infectious Disease Diagnosis and Treatment, First Affiliated Hospital, Medical College, Zhejiang University, Zhejiang, PR China.
Immunobiology. 2013 Oct;218(10):1284-92. doi: 10.1016/j.imbio.2013.04.011. Epub 2013 Apr 27.
Acute liver failure (ALF) is a highly complex syndrome characterized by devastating activation of early activation of Kupffer cells (KCs) has been implicated in the pathogenesis of ALF. However, the factors regulating KC early activation are virtually unexplored. The aim of present study was to determine the role of the intracellular high-mobility group box 1 (HMGB1) in modulating the early activation of KCs during ALF. The intravenous injection of Concanavalin A (Con A) was used to establish a mouse model of ALF. The dynamic pro-inflammatory properties and MHC II expression of KCs were measured by qRT-PCR and flow cytometry. HMGB1 expression in KCs was measured by qRT-PCR and Western blotting. The immunofluorescence was implemented to determine the relocation of HMGB1 in KCs, and the siRNA against HMGB1 was utilized to assess the impact of HMGB1 on KC pro-inflammatory properties. The peak of pro-inflammatory cytokines production and MHC II expression in KCs appeared at the early stage of ALF. The up-regulation of HMGB1 expression and the translocation of HMGB1 in KCs were in parallel with the early activation of KCs. The blockade of intracellular HMGB1 expression caused by siRNA significantly inhibited the production of KC-derived pro-inflammatory cytokines, and led to a down-regulation of MAP kinase activation in KCs. The self-derived HMGB1 is an "early alarmin" of KC activation during Con A-induced ALF. HMGB1 might be a potential target for cell-specific strategy in ALF.
急性肝衰竭（ALF）是一种高度复杂的综合征，其特征为早期库普弗细胞（KCs）的破坏性激活。然而，调节 KC 早期激活的因素实际上尚未得到探索。本研究旨在确定细胞内高迁移率族蛋白 B1（HMGB1）在调节 ALF 期间 KC 早期激活中的作用。通过静脉注射刀豆蛋白 A（Con A）建立小鼠 ALF 模型。通过 qRT-PCR 和流式细胞术测量 KCs 的动态促炎特性和 MHC II 表达。通过 qRT-PCR 和 Western blot 测量 KCs 中的 HMGB1 表达。实施免疫荧光以确定 HMGB1 在 KCs 中的重定位，并用 HMGB1 的 siRNA 评估 HMGB1 对 KC 促炎特性的影响。在 ALF 的早期阶段，KCs 中促炎细胞因子的产生和 MHC II 表达达到高峰。HMGB1 表达的上调和 KCs 中 HMGB1 的易位与 KCs 的早期激活平行。HMGB1 的 siRNA 阻断细胞内 HMGB1 表达显著抑制 KC 来源的促炎细胞因子的产生，并导致 KCs 中 MAP 激酶激活的下调。自分泌的 HMGB1 是 Con A 诱导的 ALF 中 KC 激活的“早期警报素”。HMGB1 可能是 ALF 中细胞特异性策略的潜在靶标。
